Neuroinflammation in World Trade Center responders at midlife: A pilot study using [18F]-FEPPA PET imaging

Abstract

Background Neuroinflammation has long been theorized to arise from exposures to fine particulate matter and to be modulated when individuals experience chronic stress, both of which are also though to cause cognitive decline in part as a result of neuroinflammation. Objectives Hypothesizing that neuroinflammation might be linked to experiences at the World Trade Center (WTC) events, this study explored associations between glial activation and neuropsychological measures including post-traumatic stress disorder (PTSD) symptom severity and WTC exposure duration. Methods Translocator protein 18-kDa (TSPO) is overexpressed by activated glial cells, predominantly microglia and astrocytes, making TSPO distribution a putative biomarker for neuroinflammation. Twenty WTC responders completed neuropsychological assessments and in vivo PET brain scan with [ 18 F]-FEPPA. Generalized linear modeling was used to test associations between PTSD, and WTC exposure duratiioni as the predictor and both global and regional [ 18 F]-FEPPA total distribution volumes as the outcomes. Result Responders were 56.0 ​± ​4.7 years-old, and 75% were police officers on 9/11/2001, and all had at least a high school education. Higher PTSD symptom severity was associated with global and regional elevations in [ 18 F]-FEPPA binding predominantly in the hippocampus ( d ​= ​0.72, P ​= ​0.001) and frontal cortex ( d ​= ​0.64, P ​= ​0.004). Longer exposure duration to WTC sites was associated with higher [ 18 F]-FEPPA binding in the parietal cortex. Conclusion Findings from this study of WTC responders at midlife suggest that glial activation is associated with PTSD symptoms, and WTC exposure duration. Future investigation is needed to understand the important role of neuroinflammation in highly exposed WTC responders.

Cortical complexity in world trade center responders with chronic posttraumatic stress disorder

“…Indeed, studies have documented disruptions in white matter connectivity and integrity in trauma and PTSD populations [ 119 – 124 ], which has been proposed to have an underlying etiology due to increased neuroinflammation due to psychosocial stress [ 125 – 132 ], with accelerated brain senescence [ 133 – 135 ], and that normal brain aging is associated with reduced cortical complexity [ 39 , 58 – 61 ]. Coupled with our own studies that have identified increased neuroinflammation in responders with chronic WTC-PTSD [ 68 , 136 – 138 ], we therefore propose that one possible avenue for the reduced cortical complexity observed in WTC responders with chronic PTSD in this study may be due to increased neuroinflammation from elevated psychosocial stress, which may have led to white matter atrophy, in turn leading to reduced cortical complexity through retraction of axonal tension. Future studies with WTC responders and other trauma affected populations should directly interrogate FD analysis, and if possible, integrate diffusion tensor imaging analyses of white matter integrity from MRI, along with concurrent Positron Emission Tomography (PET) biomarkers of neuroinflammation, such as the Translocator protein 18-kDa (TSPO) ligand FEPPA, or others.…”

Physical Functional Impairment and the Risk of Incident Mild Cognitive Impairment in an Observational Study of World Trade Center Responders

“…Previous work using neuroimaging in the WTC population has found that cognitively impaired responders with PTSD are indistinguishable in levels of cortical, 39 cerebellar, 40 and hippocampal atrophy 41 when compared with cognitively impaired responders without PTSD. However, one study of MCI noted that glial activation was related to PTSD symptom severity, 42 whereas other studies noted the presence of proteins consistent with interneuronal neurodegeneration 43 and amyloidogenesis. 44 In a neuroimaging study of cortical complexity, 45 a measure of concurrent cortical thickness, neural density, and surface convolution previously demonstrated to be negatively associated with psychiatric disorders, we demonstrated reduced fractal dimensions in WTC responders with PTSD vs those without.…”

Stress, Microglial Activation, and Mental Disorders

“…In addition, they have genetically analyzed postmortem brain samples from female PTSD patients and found reduced expression of the microglial-related genes TNFRSF14 and TSPOAP1 in addition to TSPO in the prefrontal cortex [26]. Conversely, Deri et al reported in a similar PET study that the severity of PTSD symptoms was positively correlated with TSPO expression in the hippocampus and prefrontal cortex [27]. We summarize animal, PET, and postmortem studies in Table 1.…”